Expanding Line of Therapeutic Agents for Psoriasis

Continued research has led to the development of many systemic therapeutic agents for the treatment of plaque psoriasis, including a growing list of novel biologics. These innovative biologic agents are proving to be safe and effective in addressing moderate to severe psoriasis disease, offering hope to this patient population. 

Affecting approximately 7 million individuals in the United States and 125 million worldwide, psoriasis is a chronic inflammatory skin disease that is typically characterized by scaly indurated erythematous plaques commonly located on the scalp, trunk and extensor surfaces. It can significantly impact quality of life and have far-reaching psychosocial implications in some patients. The pathogenesis of psoriasis stems from the dysregulation of the immune system, resulting in chronic inflammation and uncontrolled keratinocyte proliferation. 

Beyond the cutaneous manifestations, psoriasis is also recognized as a systemic disease and is associated with many systemic comorbidities, including psoriatic arthritis, Crohn’s disease, uveitis, obesity, type II diabetes mellitus, dyslipidemia, hypertension, and cardiovascular issues, as well as anxiety and depression. As such, the goal is to find effective treatments that can achieve and maintain a high clearance of psoriatic lesions and address the potential mosaic of comorbidities with minimal side effects.

For patients with mild psoriasis, topical agents remain the mainstay of treatment and include topical corticosteroids, vitamin D analogues, calcineurin inhibitors, and keratolytics. For those with moderate to severe psoriasis, biologics are considered first-line therapy.

The recognition of psoriasis as an auto-inflammatory disease heralded the use of systemic biological agents for treatment. It is widely viewed that the advent of the biologics in psoriasis therapy has brought promising treatment solutions to those patients suffering from moderate to severe psoriatic disease. 

Systemic Psoriasis Therapies

There are several systemic therapies currently available for patients suffering from moderate to severe psoriasis and psoriatic arthritis, including cyclosporine, methotrexate, apremilast, and retinoids, traditionally used to suppress the immune system and keratinocyte proliferation. However, biologic agents including inhibitors to tumor necrosis factor α (TNF-α) such as etanercept, infliximab, and adalimumab, interleukin (IL)-12 and IL-23 inhibitor ustekinumab, IL-17A inhibitors secukinumab and ixekizumab, IL-17RA inhibitor brodalumab, and IL-23 inhibitors guselkumab, risankizumab, tildrakizumab, and mirikizumab are just part of a growing list of tools available in the dermatologist’s armamentarium and have generated much interest among clinicians and their psoriasis patients.¹

Advancements in the immunopathogenesis of psoriasis have identified IL-23 and IL-17 as fundamental contributors in the immune pathways of the disease. According to a recent review paper², the discovery of the IL-23/T17 signaling pathway as well as the significant therapeutic advances made of late, including novel biologic therapies, have led to an improved treatment and management of psoriatic disease. 

“The discovery of the roles for interleukin-17 (IL-17) and IL-23 on the development of psoriatic disease has led to substantial increases in our understanding of the pathogenic immune events in psoriasis and has led to a paradigm shift in the treatment of this condition,” write study authors Jason J. Krueger, M.D., Ph.D., Professor and Senior Physician, Director, the Milstein Research Program, Laboratory Head, Investigative Dermatology, The Rockefeller University, New York, N.Y., and colleagues.

The FDA recently approved several inhibitors of the IL-23/IL-17 signaling axis for the treatment of psoriasis, which, according to the researchers, have proven to be very effective, resulting in significant improvements in approximately 80%-90% of psoriasis patients.

“The unprecedented success of selective IL-17 and IL-23 antagonists for the treatment of psoriasis underscores the essential nature of these cytokines in the pathogenesis of this chronic inflammatory condition,” write study authors.

Clinical Results in Biologic Therapies

In one recent paper³, Ellis et al. appraised two network meta-analyses that assessed systemic therapies for patients with moderate to severe psoriasis and found that the newer biologic therapies targeting the IL-12/23 and IL-17 axes appear to be more effective than older biologics and oral agents. 

Several clinical trials have shown novel biologic agents such as ixekizumab and guselkumab to be highly effective for patients with moderate to severe psoriasis^4-7. Recently approved by the FDA as the first selective IL-23 inhibitor for the treatment of psoriatic arthritis, guselkumab is a human IgG1λ monoclonal antibody targeting the p19 subunit of IL-23, while ixekizumab is a human monoclonal antibody targeting IL-17A. 

In a recent head-to-head study in which researchers compared the efficacy, safety and speed of response of the two biologics⁸, 1,027 patients with moderate to severe psoriasis were randomized to receive the approved dose of either subcutaneous ixekizumab or guselkumab with the primary end point of 100 percent improvement in the PASI (PASI 100) score at 12 weeks follow-up. Results showed that ixekizumab was superior to guselkumab for quickly improving signs and symptoms of moderate to severe psoriasis. The primary end point PASI 100 at week 12 was met [215/520 ixekizumab (41%); 126/507 guselkumab (25%)]. According to the study investigators, ixekizumab can offer complete skin clearance more rapidly to patients with moderate to severe psoriasis when compared to guselkumab, the IL-23 inhibitor. 

Other head-to-head clinical trials of secukinumab versus ustekinumab⁹, ixekizumab versus etanercept^4,10, and brodalumab versus ustekinumab11 have demonstrated the superior efficacy of the IL-17 antagonists. 

In another network meta-analysis study including 77 trials (34,816 patients)¹², investigators assessed the relative efficacy of IL-17 and IL-23 targeted treatments for moderate to severe psoriasis, comparing the short-term efficacy of available (or imminently available) biologic and non-biologic systemic therapies for the disease, reflected in the PASI response following treatments. Results showed that brodalumab, ixekizumab, secukinumab, guselkumab, and risankizumab were superior in efficacy to tildrakizumab, ustekinumab, all the TNF-α inhibitors, and non-biologic systemic treatments for the treatment of psoriasis. In terms of PASI 90 and PASI 100 response, data showed that brodalumab, ixekizumab, guselkumab, and risankizumab demonstrated the greatest therapeutic benefits. 

There are an increasing number of selectively targeting biologic agents that clinicians have at their disposal to better treat and manage their patients with moderate to severe psoriasis patients; however, individual characteristics vary, including the rapidity of onset, long-term-efficacy, safety profile and effects on comorbidities. Finding the ideal systemic therapy for patients with moderate to severe psoriasis and navigating among the many different and novel biologic agents can be a daunting task. Having a better understanding of each drug’s individual characteristics can help guide clinicians towards the best therapeutic choice for their psoriasis patients, resulting in minimizing disease impact and higher patient satisfaction and quality of life. 

Disclosures: None

References:

1. Armstrong AW, Read C. Pathophysiology, clinical presentation, and treatment of psoriasis: a review. JAMA. 2020; 323(19): 1945-1960. doi: 10.1001/jama.2020.4006

2. Hawkes JE, Yan BY, Chan TC, Krueger JG. Discovery of the IL-23/IL-17 signaling pathway and the treatment of psoriasis. Immunol. 2018; 201(6): 1605-1613. doi: 10.4049/jimmunol.1800013

3. Ellis AG, Flohr C, Drucker AM. Network meta-analyses of systemic treatments for psoriasis: a critical appraisal: Original Articles: Jabbar-Lopez ZK, Yiu ZZN, Ward V et al. Quantitative evaluation of biologic therapy options for psoriasis: a systematic review and network meta-analysis. J Invest Dermatol. 2017; 137:1646-54. Sbidian E, Chaimani A, Garcia-Doval I et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev 2017; 12:CD011535. Br. J. Dermatol. 2019; 180: 282–288. 

4. Griffiths CE, Reich K, Lebwohl M, van de Kerkhof P, Paul C, Menter A, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015; 386(9993): 541-551. doi: 10.1016/S0140-6736(15)60125-8

5. Paul C, Griffiths CEM, van de Kerkhof PCM, Puig L, Dutronc Y, Henneges C, et al. Ixekizumab provides superior efficacy compared with ustekinumab over 52 weeks of treatment: Results from IXORA-S, a phase 3 study. JAAD. 2019; 80: 70–79. doi: 10.1016/j.jaad.2018.06.039

6. Reich K, Griffiths CEM, Gordon KB, Papp KA, Song M, Randazzo B, et al. Maintenance of clinical response and consistent safety profile with up to 3 years of continuous treatment with guselkumab: Results from the VOYAGE 1 and VOYAGE 2 trials. JAAD. 2019; 82(4):936-945, doi: 10.1016/j.jaad.2019.11.040

7. Blauvelt A, Papp KA, Griffiths CE, Randazzo B, Wasfi Y, Shen YK, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. JAAD. 2017; 76: 405–417 

8. Blauvelt A, Papp K, Gottlieb A, et al. A head-to-head comparison of ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 12-week efficacy, safety and speed of response from a randomized, double-blinded trial. Br J Dermatol. 2020; 182(6): 1348-1358. doi: 10.1111/bjd.18851. Epub 2020 Jan 15

9. Blauvelt A, Reich K, Tsai TF, Tyring S, Vanaclocha F, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: results from the CLEAR study. JAAD.2017. 76: 60-69 

10. Gordon KB, Blauvelt A, Papp KA, Langley RG, Luger T, Ohtsuki M, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016. 375: 345–356

11. Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015. 373: 1318–1328

12. Sawyer LM, Malottki K, Sabry-Grant C, Yasmeen N, Wright E, Sohrt A, et al. Assessing the relative efficacy of interleukin-17 and interleukin-23 targeted treatments for moderate-to-severe plaque psoriasis: A systematic review and network meta-analysis of PASI response. PLoS ONE. 2019; 14: e0220868-10. doi: 10.1371/journal.pone.0220868